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Ibrutinib, Fludarabine Phosphate, Cyclophosphamide, and Obinutuzumab in Treating Patients With Chronic Lymphocytic Leukemia

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ClinicalTrials.gov Identifier: NCT02629809
Recruitment Status : Recruiting
First Posted : December 14, 2015
Last Update Posted : May 17, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase II trial studies how well ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab work in treating patients with chronic lymphocytic leukemia. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab together may work better in treating chronic lymphocytic leukemia.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Immunoglobulin Heavy Chain Locus Variable Region Mutation Small Lymphocytic Lymphoma Drug: Cyclophosphamide Drug: Fludarabine Phosphate Drug: Ibrutinib Other: Laboratory Biomarker Analysis Biological: Obinutuzumab Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: First-Line Therapy With Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (GA-101) (iFCG) for Patients With Chronic Lymphocytic Leukemia (CLL) With Mutated IGHV Gene and Non-Del(17p)
Actual Study Start Date : March 18, 2016
Estimated Primary Completion Date : March 31, 2022
Estimated Study Completion Date : March 31, 2022


Arm Intervention/treatment
Experimental: Treatment (iFCG)
See Detailed Description.
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Obinutuzumab
Given IV
Other Names:
  • Anti-CD20 Monoclonal Antibody R7159
  • GA-101
  • GA101
  • Gazyva
  • huMAB(CD20)
  • R7159
  • RO 5072759




Primary Outcome Measures :
  1. Efficacy of the combination of ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab defined as achievement of complete remission/complete remission with incomplete marrow recovery and bone marrow minimal residual disease-negative status [ Time Frame: 84 days ]
    Simon's optimal two-stage design will be employed. The proportion of patients achieving complete remission/complete remission with incomplete marrow recovery and bone marrow minimal residual disease-negative will be estimated along with the 95% confidence interval.


Secondary Outcome Measures :
  1. Bone marrow minimal residual disease-negative status [ Time Frame: 84 days ]
    Will estimate the proportion of patients achieving bone marrow minimal residual disease negative, along with the 95% confidence interval. For the patients who did not achieve primary endpoint after 3 courses of ibrutinib, fludarabine phosphate, cyclophosphamide, obinutuzumab, will estimate the rate of conversion to bone marrow minimal residual disease-negative with an additional 9 courses of ibrutinib and obinutuzumab treatment, along with the 95% confidence interval.

  2. Incidence of treatment emergent toxicities using a Bayesian design by Thall, Simon and Estey assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [ Time Frame: From the prior chemotherapy course to up to 84 days ]
    Toxicities are defined as (prolonged grade >= 3 neutropenia or thrombocytopenia) at least possibly related to the study drugs lasting > 42 days from the prior chemotherapy course; febrile neutropenia; hospitalization due to infection; early death (within first 30 days of starting treatment). Safety data will be summarized using frequency and percentage, by organ type, grade and attribution.

  3. Progression-free survival [ Time Frame: Up to 6 years ]
    The Kaplan-Meier method will be used to estimate the probabilities of progression-free survival.

  4. Overall survival [ Time Frame: Up to 6 years ]
    Log-rank tests will be used to compare subgroups of patients in terms of overall survival.

  5. Long-term incidence rate of secondary myelodysplastic syndrome/acute myeloid leukemia [ Time Frame: Up to 6 years ]
    Long-term incidence rate of secondary myelodysplastic syndrome/acute myeloid leukemia will be estimated along with 95% confidence interval.

  6. Long-term incidence rate of Richter's transformation [ Time Frame: Up to 6 years ]
    Long-term incidence rate of Richter's transformation will be estimated along with 95% confidence interval.

  7. Rate of complete remission (CR)/CR with incomplete marrow recovery (CRi) in subgroups of patients defined by fluorescence in situ hybridization (FISH) subtypes [ Time Frame: Up to 6 years ]
    Will also assess if the combination therapy results in improvement in the rate of CR/CRi in subgroups of patients defined by FISH subtypes.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with a diagnosis of CLL/small lymphocytic lymphoma (SLL), with mutated (> 2% deviation from germ line) IGHV gene, who meet criteria to initiate first-line treatment per International Workshop on CLL Working Group (IWCLL) 2008 guidelines
  • Patients must not have received prior CLL-directed therapy
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Absolute neutrophil count > 500 mL
  • Platelet count > 50,000/mL
  • Serum total bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for patients with Gilbert's disease
  • Estimated creatinine clearance >= 30 mL/min (calculated or measured by 24 hour urine collection)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
  • Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug; women of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy; men who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug
  • Free of prior malignancies for 3 years with exception of patients diagnosed with basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast, who are eligible even if they are currently treated or have been treated and/or diagnosed in the past 2 years prior to study enrolment; if patients have another malignancy that was treated within the last 2 years, such patients can be enrolled, after consultation with the principal investigator, if the likelihood of requiring systemic therapy for this other malignancy within 2 years is less than 10%, as determined by an expert in that particular malignancy at MD Anderson Cancer Center
  • Patients or their legally authorized representative must provide written informed consent
  • Prothrombin time (PT)/international normalization ratio (INR) < 1.5 x ULN
  • Partial thromboplastin time (PTT) < 1.5 x ULN
  • Activated partial thromboplastin time (aPTT) < 1.5 x ULN

Exclusion Criteria:

  • Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy, experimental therapy within 3 weeks prior to the first dose of the study drugs and/or monoclonal antibody =< 6 weeks prior to first administration of study treatment
  • Patients with del(17p) by FISH (or known tumor protein p53 [TP53] mutation)
  • Patients with unmutated (=< 2% homology with germ line) IGHV
  • Uncontrolled active systemic infection (viral, bacterial, and fungal)
  • Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, QT prolongation or familial history of QT prolongation, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
  • History of stroke or cerebral hemorrhage within 6 months
  • Patient is pregnant or breast-feeding
  • Current or chronic hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV); subjects who are positive for hepatitis B or C core antibody or hepatitis B or C surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded; Note: Patients who are receiving intravenous immunoglobulins may become seropositive for hepatitis B antibodies; these patients are allowed on the study without additional testing
  • Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune thrombocytopenia) requiring steroid therapy
  • Concurrent use of investigational therapeutic agent
  • Patients may not receive other concurrent chemotherapy, radiotherapy, or immunotherapy; localized radiotherapy to an area not compromising bone marrow function does not apply
  • Malabsorption syndrome or other condition that precludes enteral route of administration
  • Concomitant use of warfarin or other vitamin K antagonists
  • Requires treatment with a strong cytochrome P450 (CYP), family 3, subfamily A (3A) inhibitor
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study
  • Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02629809


Contacts
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Contact: Nitin Jain 713-745-6080 njain@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Nitin Jain    713-745-6080      
Principal Investigator: Nitin Jain         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Nitin Jain M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02629809     History of Changes
Other Study ID Numbers: 2015-0281
NCI-2016-00016 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2015-0281 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: December 14, 2015    Key Record Dates
Last Update Posted: May 17, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Cyclophosphamide
Fludarabine phosphate
Rituximab
Fludarabine
Obinutuzumab
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Antineoplastic Agents, Immunological